The development of apoptosis resistance is a crucial step during the pathogenesis of malignant tumors. Thus, any treatment approach overcoming apoptosis resistance may be a valuable tool in oncology. Although a variety of treatments induce apoptosis, only very few specifically trigger programmed cell death. In this regard, the class of apoptosis inducing ligands may turn out to have a considerable potential in oncology. TNF-alpha-related apoptosis-inducing ligand (TRAIL/Apo2L) is the most promising candidate, either alone or in combination with established cancer therapies, since it induces apoptosis in a wide range of malignant cells while sparing most normal tissues. Since death-receptor induced apoptosis is mainly mediated via nonmitochondrial death pathways, it is possible to induce apoptosis in cancer cell systems which mainly harbor defects within the mitochondrial death cascades. Even more so it has been shown that conventional DNA damaging approaches reduced the killing threshold for receptor induced apoptosis, making TRAIL an ideal candidate for combined approaches. Thus, combined treatments might offer the chance to enhance therapeutic efficiency and overcome resistance. In combination, additive or synergistic apoptotic responses and substantially enhanced clonogenic cell kill has been documented. Furthermore, in several settings it has been shown that combined modality teatments were effective in malignant cells, which are highly resistant to either treatment, alone. Ionizing radiation is one of the most effective modalities in oncology. Thus, it is reasonable to test, how far combinations of TRAIL with ionizing radiation may increase the efficacy. Indeed, the combination of TRAIL with ionizing radiation in several in vitro settings as well as xenograft models resulted in highly increased rates of cell kill and long-term tumor control. No increase in the rate and severity of side effects has been documented, indicating that the combination really increases the therapeutic ratio. It is important to note that TRAIL and TRAIL receptor agonistic antibodies, either as single